Oxazole compound crystal

ABSTRACT

Provided is a crystal of a specific oxazole compound that has specific inhibitory activity against PDE4, and that shows excellent stability. Specifically, provided is a crystal of an oxazole compound represented by formula (5)wherein the crystal has peaks at diffraction angles 2θ(°) of 9.6±0.2, 19.1±0.2, and 21.2±0.2 in an X-ray powder diffraction pattern measured using CuKα characteristic X-rays.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation Application of U.S. application Ser.No. 17/044,892 filed Oct. 2, 2020, which is a National Stage ofInternational Application No. PCT/JP2019/014730 filed Apr. 3, 2019,claiming priority based on Japanese Patent Application No. 2018-072717filed Apr. 4, 2018. The entire disclosures of the prior applications areincorporated herein by reference.

TECHNICAL FIELD

The present invention relates to a novel crystal of an oxazole compound,a method for producing the same, etc.

BACKGROUND ART

PTL 1 and 2 report an oxazole compound having specific inhibitoryactivity against phosphodiesterase 4 (PDE4), and a method for producingthe oxazole compound. PDE4 is predominant in inflammatory cells.Inhibition of PDE4 increases intracellular cAMP levels, and increasedcAMP levels down-regulate inflammatory response through expressionregulation of TNF-α, IL-23, or other inflammatory cytokines. Increasesin cAMP levels also increase anti-inflammatory cytokines, such as IL-10.Thus, the oxazole compound is thought to be suitable for use as ananti-inflammatory agent. For example, the oxazole compound is thought tobe useful for reducing or eliminating eczema or dermatitis, includingatopic dermatitis. PTL 3 discloses an ointment that stably contains anoxazole compound having specific inhibitory activity against PDE4, andthat can be efficiently absorbed into the skin. The disclosures of PTL 1to 3 are hereby incorporated by reference in their entirety.

CITATION LIST Patent Literature

-   PTL 1: WO2007/058338 (JP2009-515872A)-   PTL 2: WO2014/034958 (JP2015-528433A)-   PTL 3: WO2017/115780

SUMMARY OF INVENTION Technical Problem

An object of the present invention is to provide a crystal of an oxazolecompound (specifically, an oxazole compound represented by formula (5)below) that has specific inhibitory activity against PDE4, and thatshows more excellent stability.

Solution to Problem

The present inventors found a method for preparing a novel type ofpreviously unreported crystal, using a specific oxazole compound havinginhibitory activity against PDE4, and further found that the novel typeof crystal has excellent stability. The inventors made furthermodifications, and completed the present invention.

Specifically, the present invention encompasses, for example, thefollowing subject matter.

Item 1. A crystal of an oxazole compound represented by formula (5)

-   -   wherein the crystal has peaks at diffraction angles 2θ(°) of        9.6±0.2, 19.1±0.2, and 21.2±0.2 in an X-ray powder diffraction        pattern measured using CuKα characteristic X-rays.

Item 2. The crystal according to Item 1, wherein the crystal further hasone, two, or three peaks at one, two, or three diffraction angles 2θ(°)selected from the group consisting of 12.6±0.2, 22.8±0.2, and 26.0±0.2in the X-ray powder diffraction pattern measured using CuKαcharacteristic X-rays.

Item 3. The crystal according to Item 2, wherein the crystal further hasone or more peaks at one or more diffraction angles 2θ(°) selected fromthe group consisting of 10.4±0.2, 11.9±0.2, 15.0±0.2, 15.9±0.2,19.7±0.2, 24.7±0.2, and 27.6±0.2 in the X-ray powder diffraction patternmeasured using CuKα characteristic X-rays.

Item 4. A crystal of an oxazole compound represented by formula (5)

-   -   wherein the crystal has infrared absorption bands at wavenumbers        (cm⁻¹) of 3380±5, 2980±5, 1651±2, 1501±2, 1258±2, 1121±2, and        754±2 in an infrared absorption spectrum measured by a potassium        bromide disk method.

Item 5. The crystal according to any one of Items 1 to 3, wherein thecrystal has infrared absorption bands at wavenumbers (cm⁻¹) of 3380±5,2980±5, 1651±2, 1501±2, 1258±2, 1121±2, and 754±2 in an infraredabsorption spectrum measured by a potassium bromide disk method.

Item 6. The crystal according to Item 4 or 5, wherein the crystalfurther has one or more infrared absorption bands at one or morewavenumbers (cm⁻¹) selected from the group consisting of 1601±2, 1537±2,1302±2, 1234±2, 1107±2, 1026±2, and 627±2 in the infrared absorptionspectrum measured by the potassium bromide disk method.

Item 7. The crystal according to any one of Items 1 to 6, wherein thecrystal has a melting point of 75 to 90° C.

Item 8. A crystal of an oxazole compound represented by formula (5)

-   -   wherein the crystal has a melting point of 75 to 90° C.

Item 9. A pharmaceutical composition comprising the crystal according toany one of Items 1 to 8.

Item 10. The pharmaceutical composition according to Item 9, for use inthe treatment and/or prevention of eczema or dermatitis (preferablyatopic dermatitis).

Item 11 The pharmaceutical composition according to Item 9 or 10, whichis an ointment.

Advantageous Effects of Invention

A more stable crystal of a specific oxazole compound having inhibitoryactivity against PDE4 can be provided. In particular, since the crystalhas a higher melting point than a crystal of the conventional specificoxazole compound, it has high thermal stability, and is advantageous.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows an X-ray powder diffraction pattern of a type A crystal ofcompound (5), which is measured using CuKα characteristic X-rays.

FIG. 2 shows an infrared absorption spectrum of a type A crystal ofcompound (5), which is measured by a potassium bromide disk method.

FIG. 3 shows an X-ray powder diffraction pattern of a type B crystal ofcompound (5), which is measured using CuKα characteristic X-rays.

FIG. 4 shows an infrared absorption spectrum of a type B crystal ofcompound (5), which is measured by a potassium bromide disk method.

DESCRIPTION OF EMBODIMENTS

Embodiments of the present invention are detailed below.

The crystal of the oxazole compound in the present invention includes acrystal of the oxazole compound represented by formula (5) below.

The oxazole compound has specific inhibitory activity against PDE4, andis effective as an anti-inflammatory agent etc. In this specification,the oxazole compound represented by formula (5) is sometimes referred toas compound (5). Compound (5) is N-[2-(4-difluoro methoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]-2 ethoxybenzamide.

Compound (5) can be produced by a known method (for example, a methoddescribed in any one of PTL 1 to 3). However, crystal forms of compound(5) produced by known methods are different from the crystal form ofcompound (5) encompassed in the present invention. In thisspecification, the former crystal form is sometimes referred to as typeA, and the latter crystal form is sometimes referred to type B.Specifically, the crystal of compound (5) produced by a known method isa type A crystal, and the crystal of compound (5) encompassed in thepresent invention is a type B crystal.

The type B crystal is a crystal of compound (5) having one or more ofthe following features. Among features (i) to (iii) below, the type Bcrystal preferably has at least one feature, more preferably has atleast two features (i.e., features (i) and (ii), features (ii) and(iii), or features (iii) and (i)), and still more preferably has allthree features.

Feature (i): Characteristic X-Ray Powder Diffraction Pattern

The type B crystal preferably has peaks at diffraction angles 2θ(°) of9.6±0.2, 19.1±0.2, and 21.2±0.2 in the X-ray powder diffraction patternmeasured by CuKα characteristic X-rays. Of these three peaks, theintensity of the peak at a diffraction angle 2θ(°) of 19.1±0.2(sometimes referred to as peak [12]) is preferably the lowest. Theintensity of the peak at a diffraction angle 2θ(°) of 21.2±0.2(sometimes referred to as peak [16]) is preferably the largest. The peakat a diffraction angle 2θ(°) of 9.6±0.2 is sometimes referred to as peak[2].

The rate of the intensity of peak [12] and peak [16](peak [16]/peak[12]) is preferably about 1.5 to 2.5, more preferably about 1.6 to 2.4or 1.7 to 2.3, and still more preferably about 1.8 to 2.2 or about 1.9to 2.1. The rate of the intensity of peak [12] and peak [2] (peak[2]/peak [12]) is preferably about 1.5 to 1.75.

It is further preferable to have one, two, or three peaks at one, two,or three diffraction angles 2θ(°) selected from the group consisting of12.6±0.2, 22.8±0.2, and 26.0±0.2, in addition to the above three peaks(peaks [2], [12], and [16]). The peak at a diffraction angle 2θ(°) of12.6±0.2 is sometimes referred to as peak [6]. The peak at a diffractionangle 2θ(°) of 22.8±0.2 is sometimes referred to as peak [18]. The peakat a diffraction angle 2θ(°) of 26.0±0.2 is sometimes referred to aspeak [20].

In the most preferable embodiment, the type B crystal has all of peaks[6], [18], and [20], in addition to peaks [2], [12], and [16]. In thiscase, the intensity of each of peaks [6], [18], and [20] is preferablylower than the intensity of peak [12]. In addition, the intensity ofpeak [20] is preferably the largest among the intensity of peaks [6],[18], and [20].

In addition to the above four to six peaks (three peaks of peaks [2],[12], and [16]; and one, two, or three peaks selected from the groupconsisting of peaks [6], [18], and [20]), it is further preferable tohave one or more peaks at one or more (2, 3, 4, 5, 6, or 7) diffractionangles 2θ(°) selected from the group consisting of 10.4±0.2, 11.9±0.2,15.0±0.2, 15.9±0.2, 19.7±0.2, 24.7±0.2, and 27.6±0.2. The intensity ofeach of these one to seven peaks is preferably lower than the intensityof each the four to six peaks mentioned above. Particularly preferred isa type B crystal having peaks [2], [12], [16], and peaks [6], [18], and[20]; as well as peaks at diffraction angles 2θ(°) of 10.4±0.2,11.9±0.2, 15.0±0.2, 15.9±0.2, 19.7±0.2, 24.7±0.2, and 27.6±0.2.

Feature (ii): Characteristic Infrared Absorption Spectrum

The type B crystal preferably has infrared absorption bands atwavenumbers (cm⁻¹) of 3380±5, 2980±5, 1651±2, 1501±2, 1258±2, 1121±2,and 754±2 in the infrared absorption spectrum measured by a potassiumbromide disk method. Of these infrared absorption bands, an infraredabsorption band at a wavenumber (cm⁻¹) of 1651±2 is particularly a bandcharacteristic to the type B crystal. These infrared absorption bandsare derived from infrared absorption of characteristic functional groupspresent in compound (5), which is more specifically explained below.(The wavelength described to the right of the slash “/” in the followingdescription is the wavelength of the infrared absorption band of thetype A crystal described below.)

-   -   3380 (cm⁻¹): Secondary amide N—H Stretching vibration    -   2980 (cm⁻¹): —CH₂ Stretching vibration    -   1651/1643 (cm⁻¹): Amide C═O Stretching vibration    -   1501/1503 (cm⁻¹): Aromatic C═C Stretching vibration    -   1258/1261, 1121/1119 (cm⁻¹): —CF₂ Stretching vibration    -   754/758 (cm⁻¹): Benzene C—H Out-of-plane bending vibration

In addition to such characteristic infrared absorption bands, the type Bcrystal preferably has one or more infrared absorption bands at one ormore (2, 3, 4, 5, 6, or 7) wavenumbers (cm⁻¹) selected from the groupconsisting of 1601±2, 1537±2, 1302±2, 1234±2, 1107±2, 1026±2, and 627±2.

In the infrared absorption spectrum, the error of the wavenumber (cm⁻¹)of one or more (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13) infraredabsorption bands may be ±4, ±3, ±2, or ±1.

Feature (iii): Characteristic Melting Point

The melting point of the type B crystal is preferably 75 to 90° C. Thelower limit of this range may be 76° C., 77° C., 78° C., 79° C., or 80°C. The upper limit of this range may be 89° C., 88° C., 87° C., 86° C.,85° C., or 84° C. The melting point is preferably 77 to 88° C., morepreferably 78 to 86° C., still more preferably 79 to 85° C., andparticularly preferably 80 to 84° C.

The melting point is the value measured according to Method 1 in Section2.60 of the Japanese Pharmacopoeia, Seventeenth Edition.

The type B crystal can be prepared by allowing the type A crystal tostand for a long period of time at a temperature higher than roomtemperature. More specifically, the type B crystal can be prepared byallowing the type A crystal to stand at preferably 40 to 60° C., morepreferably 45 to 55° C., and still more preferably at 48 to 52° C., forpreferably 3 months or more, and more preferably 4 months or more or 5months or more. The upper limit of the static period is not particularlylimited, as long as the type B crystal can be obtained; and it is, forexample, about 6 or 7 months. The type A crystal is preferably allowedto stand in sealed or tightly sealed containers. Moreover, the type Acrystal is preferably allowed to stand under a condition that isunaffected by light (e.g., a light-shielding condition; morespecifically, in a light-blocking amber bottle).

The type A crystal can be prepared by a known method as described above,for example, by a method described in any of PTL 1 to 3. Although thereis no particular limitation, the type A crystal can be prepared bypreparing compound (5) according to the reaction formula described inPTL 3, and precipitating the crystal of compound (5). The resultingprecipitated crystal can be dried, and then used as the type A crystal.The dried type A crystal is particularly preferred as a type A crystalthat is allowed to stand at a temperature higher than room temperaturefor a long period of time, and used for preparing the type B crystal.

DIPEA: Diisopropylethylamine, CPME: Cyclopentyl methyl ether, DMF:N,N-dimethylformamide, 2-EBA: 2-Ethoxybenzoic acid, WSC:1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride

The X-ray powder diffraction pattern, infrared absorption spectrum, andmelting point of the type A crystal are described below. The type Acrystal particularly has characteristic peaks at diffraction angles2θ(°) of 5.8±0.2, 11.6±0.2, 17.1±0.2, 23.1±0.2, and 26.1±0.2 in theX-ray powder diffraction pattern measured using CuKα characteristicX-rays. The type A crystal may further have one or more peaks at one ormore diffraction angles 2θ(°) selected from the group consisting of10.2±0.2, 13.2±0.2, 16.1±0.2, 18.5±0.2, 22.2±0.2, and 26.7±0.2. The typeA crystal particularly has infrared absorption bands at wavenumbers(cm⁻¹) of 3380±5, 2980±5, 1643±2, 1503±2, 1261±2, 1119±2, and 758±2 inthe infrared absorption spectrum measured by a potassium bromide diskmethod. The type A crystal may further have one or more infraredabsorption bands at one or more wavenumbers (cm⁻¹) selected from thegroup consisting of 1601±2, 1537±2, 1296±2, 1229±2, 1047±2, 939±2, and617±2. The melting point of the type A crystal (measured in accordancewith Method 1 in Section 2.60 of the Japanese Pharmacopoeia, SeventeenthEdition) is about 56 to 60° C.

The present invention also comprises a pharmaceutical compositioncontaining the type B crystal. The pharmaceutical composition, forexample, contains a pharmaceutically acceptable carrier and the type Bcrystal. Such carriers are not particularly limited, and known carrierscan be used. The pharmaceutical composition is sometimes referred to asthe pharmaceutical composition of the present invention.

The pharmaceutical composition of the present invention is particularlyeffective for reducing or eliminating eczema and dermatitis, inparticular for reducing or eliminating atopic dermatitis. Thepharmaceutical composition of the present invention can be used as apreventing agent and/or treating agent of these diseases.

The form of the pharmaceutical composition of the present invention isnot particularly limited. Examples include externally applied agents forthe skin, oral formulations, injections, and the like. Of these,externally applied agents for the skin are preferred, and ointments areparticularly preferred. In an ointment, it is preferable that type Bcrystal (I) is dissolved in a base component, and that the basecomponent comprises ointment base (III) and solvent (II) for dissolvingcompound (5).

More preferred is an ointment wherein solvent (II) containing dissolvedtype B crystal (I) is dissolved or dispersed in the form of droplets inointment base (III).

Type B crystal (I) may be dissolved in solvent (II) by heating. Type Bcrystal (I) is preferably dissolved by heating at a temperature higherthan the melting point of type B crystal. For example, heating anddissolving can be performed at 75° C. or higher, 76° C. or higher, 77°C. or higher, 78° C. or higher, 79° C. or higher, 80° C. or higher, 81°C. or higher, 82° C. or higher, 83° C. or higher, 84° C. or higher, 85°C. or higher, 86° C. or higher, 87° C. or higher, 88° C. or higher, 89°C. or higher, or 90° C. or higher. The upper limit of the heatingtemperature is not particularly limited, as long as the effects ofcompound (5) are attained. For example, the temperature is 100° C. orlower, 99° C. or lower, 98° C. or lower, 97° C. or lower, 96° C. orlower, 95° C. or lower, 94° C. or lower, 93° C. or lower, 92° C. orlower, or 91° C. or lower.

Although there is no particular limitation, type B crystal (I) ispresent in the ointment in an amount of preferably 0.01 to 10 parts byweight, more preferably 0.05 to 7.5 parts by weight, still morepreferably 0.1 to 5 parts by weight, per 100 parts by weight of theointment.

As stated above, type B crystal (I) is preferably dissolved in solvent(II). The solvent is preferably a polar compound that is a liquid atroom temperature. Specific examples of the solvent include ethylenecarbonate, propylene carbonate, benzyl alcohol, triacetin, diethylsebacate, diisopropyl sebacate, diethyl adipate, diisopropyl adipate,isostearic acid, olive oil, hexyldodecanol, decyl oleate, isostearylalcohol, and isopropyl myristate. Ethylene carbonate, propylenecarbonate, benzyl alcohol, and triacetin are more preferable, andpropylene carbonate and triacetin are still more preferable. Of these,propylene carbonate is preferable. These solvents can be used singly, orin a combination of two or more. In particular, it is preferable to useethylene carbonate or propylene carbonate alone, or a combination ofethylene carbonate or propylene carbonate with benzyl alcohol and/ortriacetin.

Solvent (II) is present in the ointment in an amount of preferably morethan 2 parts by weight, more preferably 2.1 parts by weight or more, andstill more preferably 2.2 parts by weight or more, per part by weight oftype B crystal (I). The upper limit of the amount of solvent (II) is notparticularly limited, as long as the effect of the present invention isproduced. For example, the upper limit is preferably 30 parts by weightor less, more preferably 20 parts by weight or less, and still morepreferably 15 parts by weight or less.

Solvent (II) is present in the ointment in an amount of preferably 0.1to 50 parts by weight, more preferably 0.2 to 25 parts by weight, andstill more preferably 0.5 to 20 parts by weight, per 100 parts by weightof the ointment.

A solution of the type B crystal in the solvent is preferably dissolvedor dispersed in the form of droplets in ointment base (III), and morepreferably dispersed in the form of droplets in ointment base (III).

Known ointment bases for use in the production of ointments can be usedas ointment base (III). Examples of ointment bases include hydrocarbons,and more specific examples include grease bases, particularly naturalwax, petroleum wax, and other hydrocarbons. Examples of natural waxinclude beeswax (e.g., unbleached beeswax, non-chemically bleachedbeeswax, and chemically bleached beeswax), and carnauba wax. Examples ofpetroleum wax include paraffin and microcrystalline wax. Examples ofother hydrocarbons include liquid paraffin and petrolatum (e.g., whitepetrolatum and yellow petrolatum). These ointment bases can be usedsingly, or in a combination of two or more.

Ointment base (III) is present in the ointment in an amount ofpreferably 5 to 5000 parts by weight, more preferably 10 to 2500 partsby weight, and still more preferably 20 to 1000 parts by weight, perpart by weight of type B crystal (I).

Ointment base (III) is present in the ointment in an amount ofpreferably 50 to 99 parts by weight, more preferably 70 to 98 parts byweight, and still more preferably 80 to 97 parts by weight, per 100parts by weight of the ointment.

Ointment base (III) preferably comprises at least beeswax. The beeswaxfor use is preferably beeswax that is not chemically bleached;including, for example, beeswax that is non-chemically bleached(non-chemically bleached beeswax), and beeswax that is not bleached(unbleached beeswax).

The beeswax is present in the ointment in an amount of preferably 0.05to 50 parts by weight, more preferably 0.1 to 40 parts by weight, andstill more preferably 0.2 to 35 parts by weight, per part by weight oftype B crystal (I).

The beeswax is present in the ointment in an amount of preferably 0.1 to10 parts by weight, more preferably 0.2 to 9 parts by weight, still morepreferably 0.4 to 8 parts by weight, even still more preferably 0.5 to7.5 parts by weight, and particularly preferably 1 to 5 parts by weight,per 100 parts by weight of the ointment.

When other ointment bases are combined with beeswax, the combination isnot particularly limited. However, for example, the combinationpreferably comprises beeswax and at least one member selected from thegroup consisting of petrolatum (preferably white petrolatum), liquidparaffin, and paraffin.

In addition to the ointment base, the ointment may comprise otheradditives for use in ointments (in particular, pharmaceuticaladditives), such as aroma components, colorants, preservatives,absorption promoters including higher alkene acids (e.g., oleic acid),or medicaments effective for treating other skin diseases.

As stated above, the ointment of the present invention is preferably anointment wherein solvent (II), in which type B crystal (I) is dissolved,is dissolved or dispersed in the form of droplets in ointment base(III). Examples of the method for producing this ointment include amethod comprising preparing a solution of component (I) in component(II), and mixing the solution with component (III) with stirring. Mixingwith stirring can be performed with, for example, a homomixer, a paddlemixer, or a combination of these mixers.

In the use of multiple types of ointment bases (component (III)), it ispreferable to mix the multiple ointment bases beforehand. In theformulation of component (III) containing multiple types of ointmentbases, it is preferable to mix the ointment bases with heating to meltthe solids, such as beeswax. For example, when beeswax and otherointment bases are used in combination, the beeswax and other ointmentbases are preferably mixed beforehand, preferably with heating.

In the case of an ointment wherein component (II), in which component(I) is dissolved, is dispersed in the form of droplets in component(III), the particle size of the droplets observed with a polarizingmicroscope is 100 μm or less, preferably about 40 μm or less, morepreferably about 25 μm or less, and still more preferably about 20 μm orless. In particular, there exist preferably no droplets having aparticle size of more than 100 μm, more preferably no droplets having aparticle size of more than 40 μm, still more preferably no dropletshaving a particle size of more than 25 μm, and even still morepreferably no droplets having a particle size of more than 20 μm. Adesired mean particle size of the droplets is achieved by adjusting thestirring rate at which the solution is mixed with component (III) withstirring.

In this specification, the term “comprising” includes “consistingessentially of” and “consisting of.” The present invention covers allcombinations of the elements described in this specification.

The characteristics (properties, structures, functions, etc.) that areexplained in the embodiments of the present invention can be combined inany manner to specify the subject matter included in the presentinvention. Specifically, the present invention covers all of the subjectmatter that includes various combinations of the combinablecharacteristics described in this specification.

Examples

The present invention is described below in more detail. However, thepresent invention is not limited to the following Examples. In thefollowing reaction schemes, when a compound is denoted numerically, thecompound may be referred to as “compound (numerical number).” Forexample, a compound denoted as “3” may be referred to as “compound (3).”Further, in the following reaction schemes, the compound denoted as “5”is the same as compound (5) described above.

Synthesis of Oxazole Compound (Type A Crystal)

Compound (5) (white powder) was prepared in accordance with the methoddisclosed in Example 352 of PTL 1 (WO2007/058338).

Data of Compound (5)

N-({2-[4-(difluoromethoxy)-3-isopropoxyphenyl]oxazol-4-yl}methyl)-2-ethoxybenzamide:white powder.

¹H NMR (400 MHz, CDCl3): δ=8.56 (br s, 1H, NH), 8.23 (dd, J=7.6 Hz, 1.6Hz, 1H, ArH), 7.66 (s, 1H, ArH), 7.63 (d, J=2.0 Hz, 1H, ArH), 7.58 (dd,J=8.4 Hz, 2.0 Hz, 1H, ArH), 7.44-7.39 (m, 1H, ArH), 7.21 (d, J=8.0 Hz,1H, ArH), 7.08-7.04 (m, 1H, ArH), 6.94 (d, J=8.0 Hz, 1H, ArH), 6.61 (t,J=75.2 Hz, 1H, CHF₂), 4.68 (sept, J=6.0 Hz, 1H, CH), 4.62 (d, J=6.0 Hz,2H, CH₂), 4.17 (q, J=6.93, 2H, CH₂), 1.48 (t, J=7.2 Hz, 3H, CH₃), 1.39(d, J=5.6 Hz, 6H, 2CH₃).

The X-ray powder diffraction pattern of the obtained white powder ofcompound (5) was measured using CuKα characteristic X-rays. Morespecifically, the measurement was conducted under the followingconditions.

Measurement device—XRD-6000 (Shimadzu Corporation)

Operating conditions—Voltage: 35.0 kV, Current: 20.0 mA,

Sampling Pitch: 0.0200°

FIG. 1 and Table 1 show the measurement results.

TABLE 1 peak 2Theta d FWHM Intensity Integrated Int no. no. (deg) (A)I/I1 (deg) (Counts) (Counts) # Strongest 3 peaks 1 4 11.5469 7.65742 1000.2406 869 11021 2 19 23.0346 3.85799 63 0.3511 544  11213* 3 21 25.95973.42952 30 0.3355 262  4458 # Peak Data List 1 5.8157 15.18438 19 0.1860169  1999 2 10.2509 8.62243 11 0.2728 93  1422 3 11.1800 7.90788 90.1714 77  1471 4 11.5469 7.65742 100 0.2406 869 11021 5 13.2725 6.665487 0.3450 59  1156 6 14.7100 6.01718 6 0.2600 49  759 7 15.1487 5.8439010 0.2254 85  1002 8 15.8200 5.59740 6 0.2400 48  679 9 16.1346 5.4889616 0.3827 139  2601 10 17.0431 5.19836 23 0.2738 199  3292 11 17.42005.08673 4 0.0000 39   0 12 17.7200 5.00128 6 0.2450 53  899 13 18.56864.77458 13 0.3293 116  2029 14 19.0800 4.64775 4 0.3600 35  612 1520.7400 4.27935 17 0.4300 144  2826 16 21.1400 4.19927 13 0.4134 115 2014 17 21.4800 4.13356 9 0.2216 74  844 18 22.2421 3.99362 14 0.3008124  2136 19 23.0346 3.85799 63 0.3511 544 11211 20 25.2853 3.51945 100.5627 85  2603 21 25.9597 3.42952 30 0.3355 262  4458 22 26.50003.36081 4 0.2240 35  412 23 26.7020 3.33585 10 0.3040 90  1212 2427.6400 3.22473 3 0.2000 26  351 25 28.0070 3.18331 4 0.2740 39  598 2629.2200 3.05386 5 0.4480 41  855 27 29.4600 3.02952 5 0.1658 46  405 2831.1971 2.86468 5 0.3408 46  1047

The infrared absorption spectrum of the obtained white powder ofcompound (5) was measured by the potassium bromide disk method. Morespecifically, the measurement was conducted under the followingconditions.

Measurement device—IR Prestige-21 (Shimadzu Corporation)

Operating conditions—Cumulative number: 16, Resolution: 4 cm⁻¹

FIG. 2 shows the measurement results.

The melting point of the obtained white powder of compound (5) wasmeasured in accordance with Method 1 in Section 2.60 of the JapanesePharmacopoeia, Seventeenth Edition. More specifically, the measurementwas conducted under the following conditions.

Measurement device—M-565 (BUCHI)

Operating conditions—The white powder of compound (5) was placed in adry capillary tube to form a layer with a thickness of 2.5 to 3.5 mm.The bath fluid was gradually heated to 48° C., and the capillary tubecontaining the white powder was inserted. Subsequently, the temperaturewas increased at a rate of about 3° C. per minute, and when thetemperature reached 53° C., the temperature was increased at a rate ofabout 1° C. per minute; the samples were then observed.

The measurement results confirmed that the melting point of the whitepowder (type A crystal) of compound (5) was about 56 to 60° C.

The crystals of compound (5) prepared in accordance with the methoddisclosed in PTL 2 (WO2014/034958) (in particular, Example 1 (1-10):compound 1) and the method disclosed in PTL 3 (WO2017/115780) (inparticular, Production Example 4 (compound (11)) using the thus-obtainedtype A crystal as a seed crystal both also had the same characteristicsas above, and thus were considered to be type A crystals.

Type B Crystal Preparation 1

The type A crystal (12 g) was placed in an amber glass bottle. The glassbottle was sealed, and stored for 3 months in an incubator (50±2° C.).The X-ray powder diffraction pattern and the infrared absorptionspectrum of the powder (crystal) collected after storage were measuredas above. FIG. 3 and Table 2 show the X-ray powder diffraction pattern,and FIG. 4 shows the infrared absorption spectrum. The melting point wasalso measured as in the above method, except that “48° C.” was changedto “72° C.,” and “53° C.” was changed to “77° C.” The melting point wasfound to be about 80 to 84° C.

TABLE 2 peak 2Theta d FWHM Intensity Integrated Int no. no. (deg) (A)I/I1 (deg) (Counts) (Counts) # Strongest 3 peaks 1 16 21.1479 4.19772100 0.2253 876 9915 2 2 9.5562 9.24764 82 0.2303 717 8537 3 12 19.06004.65258 50 0.2757 437 5663 # Peak Data List 1 9.1600 9.64672 6 0.2200 541412 2 9.5562 9.24764 82 0.2303 717 8537 3 10.3752 8.51941 11 0.2162 991244 4 11.5800 7.63560 3 0.2934 28 456 5 11.8351 7.47159 11 0.1837 97881 6 12.5573 7.04346 22 0.2259 194 2554 7 14.9711 5.91282 9 0.2178 831024 8 15.6200 5.66862 5 0.2134 42 500 9 15.8818 5.57576 12 0.2487 1091469 10 17.5600 5.04649 4 0.2500 37 688 11 18.5400 4.78189 4 0.2600 34765 12 19.0600 4.65258 50 0.2757 437 5663 13 19.3000 4.59526 26 0.1952224 2180 14 19.6942 4.50416 14 0.2776 127 1874 15 20.8600 4.25500 250.2542 216 3633 16 21.1479 4.19772 100 0.2253 876 9915 17 22.36003.97283 11 0.2734 94 1318 18 22.7003 3.91404 24 0.2776 206 3116 1924.6375 3.61050 7 0.3250 63 1121 20 25.9103 3.43595 36 0.2628 312 442721 26.2200 3.39607 17 0.2284 148 1807 22 27.5105 3.23962 6 0.2510 52 80723 28.4600 3.13366 3 0.2400 30 413 24 29.2200 3.05386 3 0.2200 30 288 2529.4183 3.03372 4 0.2367 38 463 26 31.6000 2.82907 3 0.3000 27 628 2731.8200 2.81001 3 0.3466 30 466 28 34.1400 2.62418 4 0.5200 36 818 2934.3200 2.61082 4 0.1534 37 255

These results revealed that the X-ray powder diffraction pattern, theinfrared absorption spectrum, and the melting point of the crystalcollected after storage were all different from those of the type Acrystal. This crystal was named “type B crystal.”

As described above, the type B crystal has a melting point higher thanthat of the type A crystal. This fact confirmed that the type B crystalhas more excellent thermal stability. Before this analysis, arecrystallization method was performed using various solvents to searchfor crystals with more excellent stability than the type A crystal;however, different crystal types could not be found. Surprisingly,however, it was clarified that the type B crystal, which has higherstability (in particular, thermal stability), can be prepared byallowing the type A crystal to stand at a temperature higher than roomtemperature for a long period of time.

Type B Crystal Preparation 2

Analysis was conducted to further prepare the type B crystal using theobtained type B crystal as a seed crystal. More specifically, the type Bcrystal was prepared as follows, in accordance with the method disclosedin PTL 3 (WO2017/115780).

20.00 g (66.8 mmol) of compound (1) and 17.28 g (134 mmol) ofdiisopropylethylamine were added to 300 mL of ethyl acetate, and themixture was cooled. 11.48 g (100 mmol) of methanesulfonyl chloride waspoured in and stirred at 10 to 30° C. for 1 hour. 17.41 g (200 mmol) oflithium bromide was added thereto, and the mixture was stirred at 20 to35° C. for 1 hour. 100 mL of water was added to the reaction solution,and the mixture was separated, followed by concentration of the organiclayer under reduced pressure. 300 mL of ethyl acetate was added to theconcentrated residue to dissolve the residue, and the solution was againconcentrated under reduced pressure. 200 mL of N,N-dimethylformamide and17.33 g (93.6 mmol) of potassium phthalimide were added to theconcentrated residue, and reacted at 75 to 85° C. for 1 hour. 200 mL ofwater was added to the reaction solution to precipitate crystals. Theprecipitated crystals were collected by filtration and dried at 80° C.,thereby obtaining 27.20 g (yield: 95.01%) of compound (3).

20.00 g (46.7 mmol) of compound (3), 40 mL of a 40% methylamine aqueoussolution, 40 mL of methanol, and 100 mL of water were mixed and reactedfor 30 minutes under reflux. 200 mL of cyclopentyl methyl ether (CPME)and 20 mL of a 25% sodium hydroxide aqueous solution were added to thereaction solution, and the temperature was adjusted to 65 to 75° C.,followed by separation. A mixture of 100 mL of water and 20.00 g ofsodium chloride was added to the organic layer, and the temperature wasadjusted to 65 to 75° C. again, followed by separation. 5 mL ofconcentrated hydrochloric acid was added to the organic layer toprecipitate crystals. The precipitated crystals were collected byfiltration, thereby obtaining 27.58 g of compound (4) as a wet crystal.

The wet crystal (46.7 mmol) of compound (4) was mixed with 120 mL ofethyl acetate and 7.1 mL (51.4 mmol) of triethylamine, and stirred at 20to 30° C. for 1 hour. 10.09 g (60.7 mmol) of 2-ethoxybenzoic acid and11.63 g (60.7 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (WSC) were added to the reaction solution, and reacted at20 to 30° C. for 1 hour. 60 mL of water and 6 mL of concentratedhydrochloric acid were added to the reaction solution, and thetemperature was adjusted to 40 to 50° C., followed by separation. 60 mLof water and 6 mL of a 25% sodium hydroxide aqueous solution were addedto the organic layer, and the temperature was adjusted to 40 to 50° C.again. The mixture was separated, and the organic layer was concentratedunder reduced pressure. 50 mL of ethanol, 20 mL of water, 6 mL of a 25%sodium hydroxide aqueous solution, and 0.6 g of activated carbon wereadded to the concentrated residue, and the mixture was refluxed for 30minutes. The activated carbon was removed by filtration, and thefiltrate was washed with 12 mL of ethanol. The filtrate was cooled, and10 mg of the type B crystal (a seed crystal) was added thereto toprecipitate crystals. The precipitated crystals were collected byfiltration and dried at 60° C., thereby obtaining 18.38 g (88.18%) ofcompound (5).

The X-ray powder diffraction pattern, the infrared absorption spectrum,and the melting point of the obtained crystal were measured as above.The results were all the same as the results above of the type Bcrystal. This confirmed that the type B crystal can be directlysynthesized by using the type B crystal as a seed crystal, without thenecessity of preparing the type B crystal by using the type A crystal.

The invention claimed is:
 1. A method for producing a pharmaceuticalcomposition containing a compound represented by formula (5),

the method comprising dissolving a crystal of the compound, wherein thecrystal has peaks at diffraction angles 2θ(°) of 9.6±0.2, 12.6±0.2,19.1±0.2, 21.2±0.2, and 22.8±0.2 in an X-ray powder diffraction patternmeasured using CuKα characteristic X-rays.
 2. The production methodaccording to claim 1, wherein the crystal further has a peak atdiffraction angle 2θ(°) of 26.0±0.2 in the X-ray powder diffractionpattern measured using CuKα characteristic X-rays.
 3. The productionmethod according to claim 2, wherein the crystal further has one or morepeaks at one or more diffraction angles 2θ(°) selected from the groupconsisting of 10.4±0.2, 11.9±0.2, 15.0±0.2, 15.9±0.2, 19.7±0.2,24.7±0.2, and 27.6±0.2 in the X-ray powder diffraction pattern measuredusing CuKα characteristic X-rays.
 4. The production method according toclaim 1, wherein the crystal has infrared absorption bands atwavenumbers (cm⁻¹) of 3380±5, 2980±5, 1651±2, 1501±2, 1258±2, 1121±2,and 754±2 in an infrared absorption spectrum measured by a potassiumbromide disk method.
 5. The production method according to claim 1,wherein the crystal has a melting point of 75 to 90° C.
 6. Theproduction method according to claim 1, comprising dissolving thecrystal in a solvent by heating at a temperature equal to or higher thanthe melting point of the crystal.
 7. The production method according toclaim 6, comprising dissolving the crystal in a solvent by heating at atemperature of 85° C. or higher and 91° C. or lower.
 8. The productionmethod according to claim 1, comprising dissolving the crystal in asolvent, and mixing the solvent containing dissolved crystal with anointment base.
 9. The production method according to claim 8, whereinthe solvent containing dissolved crystal in the pharmaceuticalcomposition is dissolved or dispersed in the form of droplets in theointment base.
 10. The production method according to claim 8, whereinthe solvent is a polar compound that is a liquid at room temperature.11. The production method according to claim 8, wherein the ointmentbase comprises a hydrocarbon.
 12. The production method according toclaim 8, wherein the ointment base comprises at least beeswax.
 13. Theproduction method according to claim 9, wherein the droplets have a meanparticle size of 100 μm or less.
 14. The production method according toclaim 1, which is a method for producing an ointment.